Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder: Clinical Evidence, Neurobiological Mechanisms, and Treatment Perspectives.

Major depressive disorder (MDD) remains one of the leading causes of disability worldwide, and a substantial proportion of patients do not achieve remission with standard pharmacological treatments. In this context, repetitive transcranial magnetic stimulation (rTMS) has gained increasing clinical recognition as a non-invasive alternative with a growing evidence base. We conducted a narrative review through a structured PubMed search combining the terms "major depressive disorder," "repetitive transcranial magnetic stimulation," "rTMS," "theta burst stimulation," and "treatment-resistant depression." We prioritized randomized controlled trials, meta-analyses, and international clinical guidelines published between 2006 and 2025, favoring sham-controlled and multisite designs. A total of 31 articles were included. The available evidence supports the use of rTMS in patients with MDD who have not responded adequately to antidepressant therapy, though response rates remain modest--approximately 29% for high-frequency protocols in controlled trials. No reliable method currently exists for predicting which patients will benefit before treatment begins. Theta burst stimulation has shown comparable efficacy to conventional protocols in shorter sessions, and accelerated paradigms, such as Stanford Neuromodulation Therapy, have yielded striking preliminary results, though replication in larger and more representative samples is still needed. Neuroimaging biomarkers, particularly resting-state connectivity measures, show promise but remain outside routine clinical reach. How to sustain response after an acute course--and for whom--remains an open and underexplored question. rTMS has earned its place in the treatment of MDD. What the field still needs to answer is who benefits most, when to introduce it, and how to keep patients well over time.